Disclosures for Dr. Bhatt

Transcription

1 Renal Denervation Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAI, FESC Executive Director of Interventional Cardiovascular Programs, BWH Heart & Vascular Center Professor of Medicine, Harvard Medical School

2 Disclosures for Dr. Bhatt Advisory Board: Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care; Chair: American Heart Association Get With The Guidelines Steering Committee; Data Monitoring Committees: Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Associate Editor), Population Health Research Institute (clinical trial steering committee), Slack Publications (Chief Medical Editor, Cardiology Today s Intervention), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor); Research Funding: Amarin, AstraZeneca, Bristol- Myers Squibb, Eisai, Ethicon, Forest Laboratories, Ischemix, Medtronic, Pfizer, Roche, Sanofi Aventis, St. Jude Medical, The Medicines Company; Unfunded Research: FlowCo, PLx Pharma, Takeda. This presentation discusses off-label and/or investigational uses of various drugs and devices. The SYMPLICITY HTN-3 trial was funded by Medtronic, Inc.

3 Outcome in Resistant HTN in REACH Kumbhani DJ, Steg PG, Cannon CP, et al...bhatt DL. EHJ 2012

4 Surgical Sympathectomy in Essential Hypertension Provided Beneficial Effect on Survival % Survival s Group 4 Group 1 Group 1 Group 2 Group 3 Group Time in Years Group 2 Survival rate of Group 1: normal population Age 43 Group 3 Surgical n=1266 Medical n=467 Patients with persistently elevated BP, minimal/no eyeground changes nor abnormalities in cerebral, cardiac, or renal nerves Groups 2-4: Patients with increasing amounts of cardiovascular disease However, surgical sympathectomy was associated with significant morbidity 1. Smithwick RH, Thompson JE. JAMA. 1953;152: Gewirtz JR, et al. Cardiol J. 2011;18:

5 Renal Nerve Anatomy Allows a Catheter-Based Approach Standard interventional technique 4-6 two-minute treatments per artery Proprietary RF Generator Automated Low-power Built-in safety algorithms

6 Renal Denervation

7 SYMPLICITY HTN-1 6 Months 1 Year 2 Years 3 Years (N = 144) (N = 132) (N = 105) (N = 88) Systolic Diastolic P < 0.01 for from baseline for all time points. Data are reported only on the patients available at each time point. Expanded results presented at the European Society of Cardiology Annual Meeting, 2013.

8 SYMPLICITY HTN-2 Sustained Reductions in the Pooled (RDN and Crossover) Group* 6 Months 12 Months 18 Months 24 Months 30 Months 36 Months N = 84 N = 80 N = 74 N = 69 N = 69 N = 40 to Fro om Baseline 36 Months (mm Hg g) Systolic Diastolic P <0.01 at all time points *Crossover patients only had 30 months post-procedure data. Whitbourn, TCT 2013

9 Multiple Unblinded Trials Show RDN Lowers Blood Pressure Medtronic EnligHTN/St Jude Vessix/Boston Sci. Maya/Covidien Recor Published Sources: 1. Lancet Lancet TCT Journal of Human HTN Circulation Clin Res Cardiol J Am Soc Nephrol Eur Heart J TCT Eurointervention EuroIntervention 2013

10 SYMPLICITY HTN-3 Trial Design 2 weeks Home BP & HTN med confirmation 2 weeks 1 M 3 M Home BP & HTN med confirmation 6M Sham Procedure Screening Visit 1 Screening Visit 2 Office SBP 160 mm Hg Full doses 3 meds No med changes in past 2 weeks No planned med changes for 6 M Office SBP 160 mm Hg 24-h ABPM SBP 135 mm Hg Documented med adherence Renal angiogram; Eligible subjects randomized Renal Denervation Bhatt DL, Kandzari DE, O Neill WW, et al...bakris GL. N Engl J Med 2014 Home BP & HTN med confirmation Pi Primary endpoint 1M 3 M 6 M M 2 weeks Patients, BP assessors, and study personnel all blinded to treatment status No changes in medications for 6 M

11 Patient Disposition 1441 subjects assessed for eligibility 535 subjects randomized Excluded: 880 not eligible for randomization 26 eligible but not randomized because randomization cap was reached 364 subjects randomly 171 subjects randomly allocated to renal allocated to sham denervation control 2 subjects died 1 subject withdrew 11 missed 6-month visit 1 subject died 1 missed 6-month visit 350 (96.2%) subjects with 6 month follow-up 169 (98.8%) subjects with 6 month follow-up Bhatt DL, Kandzari DE, O Neill WW, et al...bakris GL. N Engl J Med 2014

12 Results: Population Demographics Characteristic mean ± SD or % Renal Denervation (N=364) Sham Procedure (N=171 ) Age (years) 57.9 ± ± Male sex (%) Office systolic blood pressure (mm Hg) 180±16 180± hour mean systolic ABPM (mm Hg) 159±13 160± BMI (kg/m 2 ) 34.2 ± ± Race* (%) 0.57 African American White Medical history (%) Renal insufficiency (egfr<60 ml/min/1.73m 2 ) Renal artery stenosis Obstructive sleep apnea Stroke Type 2 diabetes Hospitalization for hypertensive crisis Hyperlipidemia Current smoking *Race also includes Asian, Native American, or other Bhatt DL, Kandzari DE, O Neill WW, et al...bakris GL. N Engl J Med 2014 P

13 Baseline Hypertensive Therapy Characteristic mean ± SD or % Renal Denervation (N=364) Sham Procedure (N=171 ) No. of antihypertensive medications 5.1 ± ± 1.4 Angiotensin-converting enzyme inhibitors % at max tolerated dose Angiotensin receptor blockers % at max tolerated dose Aldosterone antagonists Alpha-adrenergic blockers Beta blockers Calcium channel blockers % at max tolerated dose Centrally-acting acting sympatholytics Diuretics % at max tolerated dose Direct renin inhibitors Direct-acting vasodilators Bhatt DL, Kandzari DE, O Neill WW, et al...bakris GL. N Engl J Med 2014

14 Blinding Efficacy Blinding Procedure: All patients underwent renal angiography Conscious sedation Sensory isolation (e.g., blindfold and music) Lack of familiarity with procedural details and expected duration Assessed by questionnaire i at discharge and 6 months (before unblinding) Time Blinding Index* 95% CI Discharge 0.68 (0.64, 0.72) 6 Months 0.77 (0.74, 0.81) *The lower boundaries of the confidence intervals of the blinding index are both > 0.5, indicating sufficient evidence of blinding. Bhatt DL, Kandzari DE, O Neill WW, et al...bakris GL. N Engl J Med 2014

15 Primary Safety Endpoint 10% Performance Goal = 9.8% Major 8% Adverse Event 6% P< Rate 4% (MAE) 2% 1.4% 0% Renal Denervation Sham Procedure (N=364) (N=171) Difference [95% CI] P* MAE 1.4% (5/361) 0.6% (1/171) 0.8% [-0.9%, 2.5%] 0.67 *comparison of MAE to control group Bhatt DL, Kandzari DE, O Neill WW, et al...bakris GL. N Engl J Med 2014

16 Primary Efficacy Endpoint Δ = (95% CI, to 2.12) P=0.26* 200 Δ = -14.1±23.9 1±23 Δ = -11.7±25.9 P<0.001 P<0.001 ce SBP (mm Hg) mm Hg 166 mm Hg 180 mm Hg 168 mm Hg Baseline 6 Months Offi 50 0 (N=364) (N=353) Denervation (N=171) Sham (N=171) *P value for superiority with a 5 mm Hg margin; bars denote standard deviations Bhatt DL, Kandzari DE, O Neill WW, et al...bakris GL. N Engl J Med 2014

17 Powered Secondary Efficacy Endpoint Δ = (95% CI, to 1.06) P=0.98* 180 Δ = -6.8± ±15 1 Δ = -4.8± ±17 P<0.001 P< h hour mea an systolic ABPM (m mm Hg) mm Hg 152 mm Hg 160 mm Hg 154 mm Hg Baseline 6 Months 30 0 (N=360) (N=329) Denervation (N=167) Sham (N=162) *P value for superiority with a 2 mm Hg margin; bars denote standard deviations Bhatt DL, Kandzari DE, O Neill WW, et al...bakris GL. N Engl J Med 2014

18 Change in Office SBP by Tertile of Baseline Office SBP 0 <170 mm Hg mm Hg >184 mm Hg N=124 N=54 N=107 N=61 N=119 N=54 Hg) -4.5 Office SBP (mm P=0.57 Denervation Control P= P=0.13 Bhatt DL, Kandzari DE, O Neill WW, et al...bakris GL. N Engl J Med 2014

19 Results: Prespecified Subgroup Analyses * * P value for superiority with margin of 5 mm Hg Bhatt DL, Kandzari DE, O Neill WW, et al...bakris GL. N Engl J Med 2014

20 Results: Prespecified Subgroup Analyses - ABPM * * P value for superiority with margin of 5 mm Hg Bakris GL, Townsend RR, Liu M, et al...bhatt DL. JACC 2014

21 Potential Limitations Drug adherence not measured by blood levels, but adherence was measured by patient diaries at baseline and 6 months. Medication changes did occur, but results unchanged even when these patients were censored. Duration of primary endpoint may have been too short, but prior studies had found benefit by 6 months. Operator learning curve is always a possibility, but we found no relationship with procedural volume in the trial. Biological confirmation of denervation did not occur, as there is no accepted measure, but appropriate energy delivery was confirmed. Bhatt DL, Kandzari DE, O Neill WW, et al...bakris GL. N Engl J Med 2014

22 Impact of number of ablations on change in office systolic blood pressure: matched cohort analysis N=166 N=155 N=134 N=100 N=63 N=46 N=27 N=19 N=10 N=163 N=152 N=131 N=98 N=61 N=45 N=26 N=18 N= Denervation Sham Baseline SBP % CI P* 1.7( 7.1, 3.7) ( 8.6, 2.4) ( 11.3, 0.5) ( 13.9, 0.3) ( 17.4, 0.7) ( 21.8, 1.2) ( 28.8, 0.7) ( 30.0, 5.9) ( 44.6, 19.8) 0.43 *P value change in SBP for RDN compared with sham Data presented are mean (SD)

23 Impact of number of ablations on change in ambulatory systolic blood pressure: matched cohort analysis N=156 N=146 N=126 N=93 N=61 N=44 N=26 N=18 N=10 N=149 N=138 N=119 N=88 N=56 N=40 N=24 N=16 N= Denervation Sham Baseline SBP % CI P* 1.4( 5.1, 2.3) ( 5.7, 1.9) ( 8.0, 0.2) ( 9.6, 0.04) < ( 13.7, 3.1) ( 14.6, 1.5) ( 16.4, 2.7) ( 20.6, 5.1) ( 37.1, 7.0) 0.17 *P value change in SBP for RDN compared with sham Data presented are mean (SD)

24 Impact of number of ablations on change in heart rate: matched cohort analysis N=165 N=154 N=133 N=99 N=63 N=44 N=27 N=19 N=10 N=162 N=151 N=130 N=97 N=60 N=40 N=26 N=18 N= Denervation Sham Baseline HR % CI 2.5( 4.9, 0.02) 2.3 ( 4.9, 0.2) 1.5 ( 4.2, 1.3) 1.6 ( 4.7, 1.6) 0.2 ( 3.8, 4.2) 1.5 ( 6.1, 3.1) 4.9 ( 10.9,1.2) 5.5 ( 12.8, 1.9) 5.7 ( 15.9, 4.6) P* *P value change in SBP for RDN compared with sham Data presented are mean (SD)

25 Impact of number of ablations on change in pulse pressure: matched cohort analysis N=166 N=155 N=134 N=100 N=63 N=46 N=27 N=19 N=10 0 N=163 N=152 N=131 N=98 N=61 N=45 N=26 N=18 N= Denervation Sham Baseline PP % CI 0.6( 4.1, 3.0) 1.2 ( 4.8, 2.4) 2.7 ( 6.5, 1.2) 4.0 ( 8.6, 0.6) 4.6 ( 10.3, 1.2) 4.6 ( 11.5, 2.4) 7.1 ( 17.3, 3.0) 5.0 ( 17.3, 7.3) 6.1 ( 28.1, 15.8) P* *P value change in SBP for RDN compared with sham Data presented are mean (SD)

26 Systolic blood pressure change at 6 months according to ablation pattern 2 Office ABPM Home nge at 6 Months Cha N=253 N=68 N=19 N=236 N=62 N=17 N=248 N=66 N= (24.1) 17.2 (22.6) 24.3 (23.3) 28 Baseline SBP Measurements (mm Hg) 6.3 (15.2) (13.9) (16.3) 8.2 (16.3) 10.3 (20.9) 9.0 (25.5) 0 Four quadrant ablations 1 Four quadrant ablation (Either Right or Left) 2 Four quadrant ablations (Both Sides) 0four quadrant tx* Four quadrant tx four quadrant tx *1 superior, 1 inferior and 2 anterior/posterior

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31 Renal Denervation Systems Medtronic St. Jude Covidien (Maya) Boston Scientific Symplicity EnligHTN OneShot Vessix Energy RF RF RF RF Monopolar Monopolar Monopolar Bipolar (5 8 Watts) (6 Watts) (25 Watts) (~1 (1 Watts) Catheter Design Catheter with single electrode Basket with four electrodes Balloon with helical electrode and irrigation Balloon with four to eight electrode pairs Guidewire No No (0.36 mm) or (0.36 mm or 0.46 mm) Denervation Time 2 min b 6 min c 2 min d 30 sec Total Denervation Time a None of these devices are available for sale in the US. b Medtronic Presentation; c St. Jude Website. d Covidien (Maya) Presentation e ReCor Presentation *The Vessix Renal Denervation System is not available for sale in the US. 24 min 24 min 4 min 1 2 min RF=Radiofrequency

32 Multi-Electrode RDN Technology Single 4 Electrode Ablation Spacing of ~5mm Offset of ~90 deg.

33 Vessix: Occluding RF Balloon Catheter for Renal Denervation Low pressure non compliant balloon (3 atm) mitigates barotrauma Offset helical pattern of electrodes is optimized for delivery of thermal energy to adventitia Gold electrodes good thermal and electrical conductivity and each electrode is visibly radiopaque on angiogram Balloons to accommodate 3mm 7mm renal artery diameters ability to treat full range of vessel diameters including accessory renal arteries Temperature sensors at each electrode allows precise measurement and independent titration of power based on temperature *The Vessix Renal Denervation System is not available for sale in the US.

34 Novel System EnligHTN

35 The PVRD Procedure 1. Needle advancement into perivascular space 2. Ethanol injection deep into per adventitial space 3. Circumferential ethanol distribution 4. Renal nerve degeneration due to alcohol effects

36 New Data on Renal Nerve Distribution Renal nerves may have a positional bias on radial distance from arterial lumen: distal nerves are closer Distal Proximal Prior concept Uniform radial distribution Distal Proximal Current concept Non-uniform radial distribution Sakakura K, et al., JACC :634-43

37 Branch & Main Artery Treatment: Effective in Reducing Renal NE in Normotensive Swine 350 Renal Norepinephrine Levels NS Control RD Areas of Renal Denervation Kidney ng/g * * 0 Ostium Main Artery Branches Henegar et al. Am J Hypertens. 2015; doi: /ajh/hpu258

38 SPYRAL HTN Global Clinical Trial Program First Phase Includes Two Parallel Trials SPYRAL HTN-OFF MED 100 patients Sham RCT (1:1) Main body and branch ablation No specific medication requirement Focus on ABPM change at 3 months QOL data to be measured ed SPYRAL HTN-ON MED 100 patients Sham RCT (1:1) Main body and branch ablation No max tolerated dose Focus on ABPM change at 3 months QOL data to be measured Second Phase SPYRAL HTN Pivotal Based on OFF/ON trial results Cost Effectiveness Data/QOL to be measured

39 Thank You! Deepak L. Bhatt, MD, MPH Executive Director of Interventional Cardiovascular Programs, BWH Heart & Vascular Center Professor of Medicine, Harvard Medical School 1 (857) dbhatt@partners.org